The primary aim of the work that is outlined in this proposal is to develop fundamentally new principles for the rational design of antimicrobial drugs. The ultimate goal of this program is to create novel membrane-disrupting agents that can be used for the treatment of acquired immune deficiency syndrome (AIDS). A major objective of these studies is to explore sterol content, osmotic stress and bilayer curvature as 'membrane targets.' In order to obtain clear and unambiguous information, a considerable amount of effort will focus on the use of simple model systems. A second objective is to synthesize new classes of pore -forming agents that mimic the structure and function of polyene macrolide antibiotics such as amphotericin B. Specific hypotheses that are to be tested include: (i) Differences in sterol content, osmotic stress, and curvature of lipid membranes can be recognized by appropriately-designed agents and used as a basis for drug design. (ii) The recognition of sterol content, osmotic stress, and membrane curvature, can be fine-tuned by adjustment of the molecular geometry of an attacking agent. (iii) Mechanistic studies that clarify rupture and leakage pathways will greatly assist the rational design of efficacious membrane -disrupting antimicrobial drugs. Specific classes of membrane- disrupting agents that are to be synthesized include (i) amphiphiles comprised of rigid, wedge -shaped hydropbobic units attached to a hydrophilic chain, (ii) water- soluble derivatives of amphotericin B (AmpB), and (iii) amphiphilic sterol derivatives that mimic the AmpB structure. In parallel studies, the antimicrobial activity for each new compound that is to be synthesized will be evaluated and compared with its activity toward model membranes. In a broad sense, this proposal involves a combination of synthetic organic chemistry, mechanistic biomembrane studies, and in vitro antimicrobial activity measurements that is aimed at establishing fundamentally new approaches toward the design of membrane-disrupting antimicrobial agents.